Development of a universal DISC vaccine strategy against congenital cytomegalovirus

针对先天性巨细胞病毒的通用 DISC 疫苗策略的开发

• 批准号: 10595098
• 负责人: ALISTAIR MCGREGOR
• 金额: $ 66.83万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-07 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595098
• 关键词: Acceleration; Acquired Immunodeficiency Syndrome; Amniotic Sac; Animal Model; Animals; Antibodies; Antigen Targeting; Antigens; Capsid; Cavia; Cell Line; Cells; Clinic; Complex; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Development; Disease; Epithelial Cells; Epithelium; Evaluation; Fetus; Fibroblasts; Gene Expression; Glycoproteins; Guinea pig cytomegalovirus; Human; Immune; Immune response; Immunity; Immunocompromised Host; Impaired cognition; Individual; Infection; Innate Immune Response; Interferons; Intervention; Macrophage; Mental Retardation; Morbidity - disease rate; Newborn Infant; PDGFRA gene; Pathogenesis; Pathogenicity; Patients; Population; Pregnancy; Proteins; Receptor Gene; Research; Research Personnel; Risk; Route; Shapes; Study models; T cell response; Transplantation; Vaccine Design; Vaccines; Viral; Virus; Virus Diseases; Visual impairment; adaptive immune response; cell type; congenital cytomegalovirus; deafness; guinea pig model; hearing impairment; immunogenicity; improved; in utero; insight; knockout animal; knockout gene; mortality; mutant; neutralizing antibody; novel; pathogen; pregnant; pup; receptor; renal epithelium; response; timeline; trophoblast; unvaccinated; vaccine immunogenicity; vaccine strategy; vaccine trial; virus tropism

ABSTRACT Congenital CMV (cCMV) is a leading cause of hearing loss and cognitive impairment in surviving newborns. A vaccine is a high priority but an effective vaccine needs to exceed protection levels of natural convalescent immunity because of the risk of re-infection by multiple strains of HCMV. The guinea pig is the only small animal model for cCMV with disease in pups similar to humans. Previously it was demonstrated that guinea pig cytomegalovirus (GPCMV) encodes functionally similar essential viral glycoprotein complexes to HCMV, which can act as neutralizing antibody target antigens. An important correlation with HCMV is that GPCMV encodes a functional gH based pentamer complex (PC) necessary for virus tropism/entry to non-fibroblast cells, pathogenesis and cCMV. Previously, the efficacy of two non-replication competent capsid mutant GPCMV DISC (Defective Infectious Single Cycle) vaccine strains were evaluated: (1) lacking PC (DISCI); (2) encoding PC (DISCII). DISCII was more successful in neutralizing virus on epithelial cells and fully protected against cCMV when pregnant animals were challenged with wild type virus. However, a significant challenge that remains to be attained is the ability of a DISC vaccine strategy to protect against: (1) multistrain virus challenge, which is an absolute necessity for a successful HCMV vaccine; (2) provide protection against natural routes of infection. A newly isolated GPCMV strain (CRV) will be included in the studies to enable multistrain virus challenge. Modified GPCMV DISC vaccine strain will be improved for immunogenicity and correlates of immune protection determined. An important leap in the guinea pig model studies is that we will employ the first gene knockout (IFNLR1) guinea pig to evaluate the importance of IFN III in shaping immune response. The overall central hypothesis is that the DISC vaccine strategy can provide greater protection against cCMV compared to convalescent immunity and can fully protect against multiple strains of virus and natural routes of infection but vaccine requires comprehensive CMV gene expression that is potentially lacking in IE1 mutant based DISC vaccine strains. The proposed studies will provide an accelerated timeline for the realistic evaluation of a DISC vaccine strategy against cCMV.

摘要